Industrial process for the synthesis of isobutyl methyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate (nisoldipine)

ABSTRACT

Synthetic process of isobutyl methyl 1,4,-dihydro-2,6-dimethyl-4-(2-nitrophenyl)3,5-pyridine dicarboxylate (Nisoldipine) comprising on the reaction of isobutyl 2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate in an apolar solvent.

FIELD OF THE INVENTION

The present invention refers to a process for the synthesis of isobutylmethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate (Nisoldipine).

PRIOR ART

Nisoldipine is a substance pharmacologically active as calciumantagonist and antihypertensive.

Nisoldipine synthesis processes are known in the art, e.g. thosedisclosed in patents U.S. Pat. No. 4,154,839 and U.S. Pat. No.4,600,778.

Said patents describe synthetic routes leading to the formation, asNisoldipine's characteristic impurities, of the dimethylester derivative(dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate: impurity A) and of the diisobutyl ester derivative(diisobutyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate: impurity E).

In particular, basic patent U.S. Pat. No. 4,154,839 discloses that saidpreparation is carried out in an alcoholic solvent, but does not specifythe Nisoldipine chromatographic purity obtained.

Tests carried out by the Applicant according to the process disclosed inU.S. Pat. No. 4,154,839 (Example 1) showed an impurities content of theorder of 3% (as concerns impurity A) and 2% (as concerns impurity E).

Considering the great similarity between said impurities andNisoldipine, it is very difficult to purify Nisoldipine from them. Itfollows that the aforesaid yield does not correspond to the real yieldof the purified final product, obtained by complex techniques and in anycase causing a product loss in respect of the crude product obtained.

Therefore, the need was deeply felt for a new Nisoldipine synthesisprocess giving a final product of high purity especially as concerns thetwo Nisoldipine's characteristic impurities, i.e. the dimethyl esterderivative (A) and the diisobutyl ester derivative (E), and easilyexploitable on a commercial scale, being based on the use of low-costand commercially available reagents and not requiring the crudeNisoldipine purification, which is complex, costly and entails anincrease in yield losses.

SUMMARY

A new process for Nisoldipine synthesis free from the drawbacks of theprocesses known is the art has now been found.

The Applicant has surprisingly and unexpectedly found a new process forthe synthesis of isobutyl methyl1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate(Nisoldipine) comprising the reaction of isobutyl2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate in anapolar solvent, e.g. aliphatic or cycloaliphatic solvents, in particularcyclohexane and/or n-hexane, to give crude Nisoldipine, whosepurification by simple crystallisation from an acetone/water mixtureyields a Nisoldipine final product of high purity (>99.5%, by HPLC),especially as concerns the two Nisoldipine's characteristic impurities,i.e. the dimethyl ester derivative (A) and the diisobutyl esterderivative (E).

The crude Nisoldipine obtained according to the present invention can beconverted into a high-purity Nisoldipine final product by a simplepurification method, such as the crystallisation, since the degree ofpurity of the aforesaid crude Nisoldipine already exceeds 99% (by HPLC).

DETAILED DESCRIPTION OF THE INVENTION

It is therefore an object of the present invention to provide a processfor the synthesis of isobutyl methyl1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate(Nisoldipine) comprising the reaction of isobutyl2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate, addedto the reaction mixture in one single portion or portionwise, in thepresence or in the absence of 4-dimethyl aminopyridine, in an apolarsolvent, e.g. aliphatic or cycloaliphatic solvents, in particularcyclohexane and/or n-hexane, to give crude Nisoldipine, isolateddirectly from the reaction solvent or by filtration from awater/methanol mixture, after elimination of the reaction solvent bydistillation.

The crude Nisoldipine obtained through the reaction described above isover 99% pure (by HPLC) and is purified by simple crystallisation fromwater and a water soluble solvent mixture, in particular anacetone/water mixture to give a Nisoldipine final product with a highdegree of purity (>99.5% by HPLC), especially as concerns the content oftwo Nisoldipine's characteristic impurities, i.e. the dimethyl esterderivative (A) and the diisobutyl ester derivative (E).

In a preferred embodiment of the Nisoldipine synthesis process being theobject of the present invention, after reaction of isobutyl2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate in anapolar solvent to give crude Nisoldipine, said Nisoldipine is purifiedby crystallisation from water and a water soluble solvent mixture, inparticular an acetone/water mixture, to give a pure Nisoldipine finalproduct.

In a further preferred embodiment of the present invention, before thereaction of isobutyl 2-(2-nitrobenzylidene)acetoacetate with methyl3-aminocrotonate, as described above, said Nisoldipine synthesisintermediate, i.e. isobutyl 2-(2-nitrobenzylidene)acetoacetate, isobtained by reacting 2-nitrobenzaldehyde with isobutyl acetoacetate inmethylene chloride, as solvent, in the presence of a catalytic amount ofpiperidine formate at a temperature of −10° C. to 50° C., preferably of20° C. to 50° C., more preferably of 27° C. to 33° C.

The catalyst, piperidine formate, forms in situ in the reaction mixtureby addition of equimolar amounts of formic acid and piperidine.

The amount of catalyst, piperidine formate, used is 0.05–0.7 molcatalyst/mol 2-nitrobenzaldehyde, preferably 0.05–0.6 mol catalyst/mol2-nitrobenzaldehyde, more preferably 0.25 mol catalyst/mol2-nitrobenzaldehyde.

In a preferred embodiment of the invention, the intermediate obtained,i.e. isobutyl 2-(2-nitrobenzylidene)acetoacetate, is isolated in thepresence of aqueous acetic acid as solvent.

Said process of synthesis of isobutyl2-(2-nitrobenzylidene)acetoacetate, an intermediate of Nisoldipinesynthesis, is a valid alternative, easily exploitable on a commercialscale, to the processes of synthesis of said intermediate known in theart.

The following examples are conveyed by way of indication, not oflimitation, of the present invention.

EXPERIMENTAL PART EXAMPLE 1 Synthesis of isobutyl2-(2-nitrobenzylidene)acetoacetate

A reactor was fed with 2-nitrobenzaldehyde (18 kg; 0.119 kmol) andmethylene chloride (36 kg). The resultant mixture was heated to 27°–33°C., added with isobutyl acetoacetate (19.8 kg; 0.125 kmol), andsuccessively, with piperidine (2.62 kg; 0.03 kmol) and 99% formic acid(1.43 kg; 0.03 kmol). The temperature of 27°–33° C. was maintained for aperiod of 20 hrs. After that time, distilled water (9 kg) was added. Thelower organic phase was separated and the aqueous phase was eliminated.

The organic phase was concentrated in plenum at an internal temperatureof 65° C. max. The reactor was put under vacuum while distillation wascontinued at an internal temperature of 50° C. max for a period of 1 hrat least, in any case until the mass precipitated. The residue soobtained was treated with 80% acetic acid (3 kg) at 40°–50° C. andstirred at said temperature until complete dissolution. The solutionobtained was cooled to 25°–30° C. for a period of 1 hr at least, untilcomplete precipitation. The temperature was lowered to 0°–5° C. for atleast 2 hrs. Then centrifugation was performed and the precipitate waswashed with 80% acetic acid (18 kg) and then with distilled water (54kg). The solid was dried at 40°–50° C. to give 22 kg of dried isobutyl2-(2-nitrobenzylidene)acetoacetate. Yield: 63.4 %.

EXAMPLE 2 Synthesis of Nisoldipine

A reactor was fed with isobutyl 2-2(nitrobenzylidene)acetoacetate (22kg; 0.0755 kmol), 4-dimethylaminopyridine (0.55 kg), methyl3-aminocrotonate (6.1 kg; 0.053 kmol), cyclohexane (88 kg). The mass wasrefluxed (75°–85° C.) for a period of 10 hrs, then an additional amountof methyl 3-aminocrotonate (6.1 kg) was added. The reaction mass wasrefluxed (75°–85° C. ) for 16 hrs at least (during the reaction theproduct precipitated).

Distillation was performed in plenum at an internal temperature of 85°C. max, until formation of a pasty but stirrable residue. The residuewas cooled to 20°–30° C.; distilled water (11 kg) and methanol (66 kg)were added. The mixture was stirred at 20°–30° C. for a period of 15min, cooled to 10°–15° C. with stirring for 30 min at least, centrifugedand washed with methanol (16.5 kg) and then with distilled water (16.5kg). The wet solid obtained (crude Nisoldipine) was fed to a rector,added with acetone (77 kg), stirred at 20°–30° C. until dissolution,added with distilled water (40.5 kg), kept under stirring at 20°–30° C.for 1 hr at least, until complete precipitation. An additional amount ofdistilled water (9.5 kg) was added at 20°–25° C. The mixture wasmaintained under stirring at 20°–25° C. for an additional 1 hr andcentrifuged. The final solid was washed with an acetone (16.5kg)/distilled water (16.5 kg) mixture prepared separately, and then withdistilled water (22 kg). The solid was dried at 40°–50° C. to give 15.5kg dried Nisoldipine product with a degree of purity of over 99.7%(HPLC). Yield 52.9%.

1. Process for the synthesis of isobutyl methyl1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridine dicarboxylate(Nisoldipine) based on the reaction of isobutyl2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate, addedto the reaction mixture at a time or portionwise, in non-polar solvent,to give crude Nisoldipine.
 2. The process as claimed in claim 1, whereinthe non-polar solvent is selected from the group consisting of aliphaticor cycloaliphatic solvents.
 3. The process as claimed in claim 2,wherein the solvent is selected from the group consisting of cyclohexaneand/or n-hexane.
 4. The process as claimed in claim 1, wherein thereaction of isobutyl 2-(2-nitrobenzylidene)acetoacetate and methyl3-aminocrotonate is carried out in the presence of4-dimethylaminopyridine.
 5. The process as claimed in claim 1, wherein,downstream of the reaction of isobutyl2-(2-nitrobenzylidene)acetoacetate with methyl 3-aminocrotonate in anon-polar solvent to give crude Nisoldipine, said Nisoldipine ispurified by crystallisation from a water/water soluble solvent mixtureto give a pure Nisoldipine final product.
 6. The process as claimed inclaim 5, wherein the water/water soluble solvent mixture isacetone/water.